19F nuclear magnetic resonance study of fluoropyrimidine metabolism in strains of Candida glabrata with specific defects in pyrimidine metabolism.
Flucytosine (5-FC)-resistant strains were isolated from the haploid opportunistic pathogen Candida glabrata by UV-induced mutation and fluoropyrimidine selection. These strains were characterized biochemically, and the metabolism of fluorinated pyrimidines was studied by 19F nuclear magnetic resonance spectroscopy. No evidence was obtained from these studies for degradative metabolism of the fluorinated derivatives. In the parental susceptible strain of C. glabrata, 5-fluorouracil but not 5-FC was detected within the cells. 5-Fluorouracil was also present in the culture supernatant after incubation of the cells with 5-FC. The distribution of fluorinated derivatives within the 5-FC-resistant strains was consistent with their genotype. Two strains of C. glabrata which had only a partial loss of cytosine deaminase and UMP pyrophosphorylase activity had high levels of resistance to 5-FC. Both C. glabrata and Candida albicans were susceptible to 5-fluorouridine. This compound but not the anticancer drug 5-fluoro-2-deoxyuridine was shown to be transported into susceptible cells by a specific uridine permease.
Fasoli
M O
MO
Department of Biochemistry, Cambridge CB2 1QW, United Kingdom.
Kerridge
D
D
Morris
P G
PG
Torosantucci
A
A
D002175:Candida / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002478:Cells, Cultured; D043525:Cytosine Deaminase; D005437:Flucytosine / Q000378:metabolism* / Q000494:pharmacology; D005472:Fluorouracil / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009700:Nucleoside Deaminases / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D010641:Phenotype; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors; D014529:Uridine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014541:Uridine Kinase / Q000378:metabolism
D012335:RNA, Ribosomal; C001943:5-fluorouridine; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D014541:Uridine Kinase; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil; D014529:Uridine